Distinct cMET inhibitors uncover pharmacological heterogeneity in SHH medulloblastoma cell lines

The c-MET kinase signalling pathway is crucial in cerebellum development and has emerged as a potential therapeutic target for medulloblastoma treatment. Our study confirms that c-MET and its ligand HGF are highly expressed in the SHH medulloblastoma subgroup, with SHH-α and SHH-β subtypes showing the highest expression levels of both genes, respectively. HGF treatments and siRNA-mediated c-MET knockdown demonstrated the proliferative dependence of SHH MB cells on c-MET signalling. However, time-lapse microscopy revealed heterogeneous behaviours of SHH cell lines following alterations in c-MET levels. Pharmacological inhibition of c-MET signalling showed that tivantinib outperforms other c-MET inhibitors, including crizotinib and foretinib, in killing SHH medulloblastoma cells. Tivantinib induces a prolonged mitotic block followed by apoptotic death in both 2D and 3D cell culture models. Additionally, tivantinib enhances the anti-proliferative activity of vincristine, the standard of care for MB patients, specifically in DAOY cells, where the combination of vincristine and tivantinib synergistically increases the level of PARP cleavage. Moreover, we demonstrated that foretinib and crizotinib induce mitotic slippage in SHH MB cells. The use of navitoclax, a pan-BCL2 inhibitor, initiates the apoptotic program after cells fail mitosis. Taken together, these data suggest that tivantinib is a superior clinical option for SHH MB patients, whereas foretinib or crizotinib should be considered only in combination with BCL2 inhibitors.